基于疏水标签的Bcl-2/Mcl-1蛋白泛素化降解剂  

Development of hydrophobic tag-based protein degraders for Bcl-2/Mcl-1 ubiquitination degradation

作　　者：王哲明 黎怡同 王紫千 张志超 WANG Zhe-ming;LI Yi-tong;WANG Zi-qian;ZHANG Zhi-chao(School of Chemistry,Dalian University of Technology,Dalian 116024,China)

机构地区：[1]大连理工大学化学学院,辽宁大连116024

出　　处：《药学学报》2024年第11期2990-2996,共7页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82073703,82270186,82273778)。

摘　　要：Bcl-2家族中的抗凋亡蛋白Bcl-2和Mcl-1是重要的抗肿瘤靶标。本研究以一个非选择性的Bcl-2家族蛋白抑制剂为基础,设计合了4种不同结构的基于疏水标签的Bcl-2/Mcl-1蛋白泛素化降解剂S1-D1~S1-D4,在乳腺癌细胞模型MCF-7上考察了其诱导Bcl-2和Mcl-1蛋白泛素化降解和肿瘤细胞凋亡的能力。结果显示,尽管S1-D1~S1-D4均保持了对Bcl-2家族蛋白广谱的亲和力,但引入不同的连接子导致S1-D1~S1-D4实现了对Bcl-2和Mcl-1的选择性降解。其中,具有疏水烷基链的S1-D2分子对Bcl-2的降解能力最强,加入3μmol·L^(-1)时能够降解超80%的Bcl-2蛋白,而具有聚乙二醇链连接子的化合物S1-D4则表现出对Mcl-1蛋白的特异性降解,加入3μmol·L^(-1)时降解了约60%的Mcl-1蛋白。细胞毒性实验证明基于疏水标签的蛋白降解剂能够通过诱导靶蛋白的降解获得更强的肿瘤细胞杀伤活性,揭示了降解剂相比于抑制剂分子的优势。The anti-apoptotic members of Bcl-2 family proteins,Bcl-2 and Mcl-1,are considered therapeutic targets of various cancers.In this article,we developed four hydrophobic tag(HyT)-based protein degraders of Bcl-2/Mcl-1,based on a Bcl-2/Mcl-1 dual inhibitor S1-6,and tested their capability in Bcl-2/Mcl-1 degradation and apoptotic induction in MCF-7 cells.Interestingly,different linkers in the HyT degraders led to selective Bcl-2/Mcl-1 degradation,though the degraders S1-D1-S1-D4 maintained the pan-Bcl-2 family binding capacity.Among them,S1-D2 and S1-D4,two compounds bearing a hydrophobic linker or a PEG linker,were observed to potently and selectively induce the ubiquitination and proteasomal degradation of Bcl-2 and Mcl-1 in living cells,with a degradation rate of more than 80%or 60%,respectively.Moreover,the HyT-based degraders showed increased lethality of cancer cells compared to the parent inhibitor S1-6,demonstrating that the advantage of degraders to the occupancy-based inhibitors.

关 键 词：基于疏水标签的蛋白降解剂 泛素化降解 BCL-2家族蛋白 抗肿瘤 

分 类 号：R914[医药卫生—药物化学]